From document EP 0 254 032 A2 it is known that NEP inhibitors can lower blood pressure under conditions where angiotensin converting enzyme (=ACE) inhibitors as a monotherapy are relatively ineffective. Further, this document discloses that NEP inhibitors may be combined with other drugs used in the treatment of hypertension, e.g. ACE inhibitors, to enhance the effects of those drugs. Consequently, pharmaceutical compositions comprising both a NEP inhibitor and an ACE inhibitor are described.
Although the beneficial role of NEP inhibiting compounds in the treatment or prevention of cardiovascular diseases, in particular essential hypertension, pulmonary hypertension and/or congestive heart failure, is widely acknowledged today, their profile of action as a monotherapy is still suffering from certain inherent deficiencies.
In congestive heart failure, as a result of the decreased cardiac output and the increase in peripheral resistance, back-pressure phenomena of the blood occur in the pulmonary circulation and the heart itself. As a result, an increased wall tension of the heart muscle occurs in the area of the auricles and chambers. In such a situation, the heart functions as an endocrine organ and secretes, inter alia, the atrial natriuretic peptide (=ANP) into the bloodstream. Due to its marked vasodilatory and natriuretic/diuretic activity, ANP brings about both a reduction in the peripheral resistance and a decrease in the circulating blood volume. The consequence is a marked pre- and afterload decrease. This constitutes an endogenous cardioprotective mechanism. This positive endogenous mechanism is limited in that ANP has only a very short half-life in the plasma. The reason for this is that the hormone is very rapidly broken down by NEP. Therefore, pharmacological NEP inhibition rises ANP levels and thus promotes this cardioprotective mechanism.
In congestive heart failure, due to a disease-related reduced output of the heart, a reflex increase in peripheral vascular resistance occurs. As a result, the heart muscle must begin to pump against an increased afterload. In a vicious cycle, this results in increased strain on the heart and worsens the situation further. The increase in the peripheral resistance is mediated, inter alia, by the vasoactive peptide endothelin. Endothelin (=ET) is the strongest presently known endogenous vasoconstrictory substance and is formed from the precursor big endothelin (=bigET) with participation of the endothelin converting enzyme (=ECE). NEP is involved not only in the breakdown of ANP but also in the breakdown of ET.
For these reasons, a combination of compounds having NEP-inhibiting activity with compounds capable of inhibiting the endogenous endothelin producing system or compounds with dual inhibiting activities on NEP and the endogenous endothelin producing system would seem to provide added value in the therapy of cardiovascular diseases like essential hypertension, pulmonary hypertension and/or congestive heart failure. As a result of inhibition of the endogenous endothelin producing system, formation of endothelin would be prevented and thus an increase in peripheral resistance would be counteracted, to result in a relief of the strain on the heart muscle. Inhibition of the ANP degrading enzyme NEP can thus lead to higher ANP levels and an increased duration of action of ANP. This will lead to a reinforcement of the ANP-mediated endogenous cardioprotective mechanism of action. However, because NEP may also be involved in ET degradation, a pure NEP inhibition would, in addition to the desired increase in the ANP levels, also lead to an unfavorable increase in the ET levels. For this reason, a mixed profile with dually acting inhibition of NEP and of the endogenous endothelin producing system is to be regarded as particularly favorable, since it prevents both the breakdown of the natriuretically/diuretically acting ANP (by NEP-blockade), and simultaneously inhibits the formation of ET. As a result, the adverse attendant effect of pure NEP-inhibitors (increase in the endothelin levels) no longer comes to bear.
HMG CoA reductase inhibitors are pharmacologically active drug compounds which are capable of selectively inhibiting the enzyme 3-hydroxy-3-methylglutaryl-coenzyme A (=HMG-COA) reductase, the enzyme responsible for catalyzing the conversion of HMG CoA to mevalonate, which is an early and rate-limiting step in the cholesterol biosynthetic pathway. HMG CoA reductase inhibitors are therefore known to possess cholesterol lowering properties which make them valuable therapeutic agents in the treatment of vascular diseases or conditions. Several clinical studies have established that lowering certain forms of cholesterol in a mammal is an effective way to treat and prevent heart attacks, sudden death and angina pectoris, both in subjects having higher than normal levels of circulating cholesterol, as well as those having normal levels of cholesterol. Therefore lowering low-density lipoprotein (=LDL) cholesterol by administration of HMG CoA reductase inhibitors is today one of the primary objectives in the treatment of patients who have, or who are at risk of developing, cardiovascular diseases, such as atherosclerosis; cerebral infarction; coronary heart disease; myocardial infarction; restenosis, like restenosis following balloon angioplasty; and/or stroke.
However, the nature of cardiovascular, in particular hypertensive vascular, diseases is multifactorial. For example, hypertension frequently coexists with hyperlipidemia and both are considered to be major risk factors for developing cardiac disease ultimately resulting in adverse cardiac events. This clustering of risk factors is potentially due to a common mechanism. Coronary heart disease is known to be a multifactorial disease in which the incidence and severity are affected by the lipid profile, the presence of diabetes and the sex of the subject. Incidence is also affected by smoking and left ventricular hypertrophy which is secondary to hypertension. To meaningfully reduce the risk of coronary heart disease, it is therefore important to manage the entire risk spectrum. For example, hypertension intervention trials have failed to demonstrate full normalization in cardiovascular mortality due to coronary heart disease. Treatment with cholesterol synthesis inhibitors in patients with and without coronary artery disease reduces the risk of cardiovascular morbidity and mortality. Further, the use of a fixed, preferably low-dose combination agent potentially also offers lower doses of each component than those that may be necessary with monotherapy, thus reducing the risks of dose-dependent adverse events and associated compliance problems. Further, patient compliance with the management of hypertension is generally better than patient compliance with hyperlipidemia. It would therefore be advantageous for patients to have a combinatorial, preferably a single, therapy which treats both of these conditions.
Compounds with a dually acting combined inhibitory effect on NEP and the endogenous endothelin producing system, i.e. benzazepine-, benzoxazepine- and benzothiazepine-N-acetic acid derivatives, are known from document EP 0 733 642 A1 (=U.S. Pat. No. 5,677,297). Further favorable pharmacological properties of compounds falling within the structural scope of EP 0 733 642 A1 are known from documents EP 0 830 863 A1 (=U.S. Pat. No. 5,783,573), WO 00/48601 A1 (=U.S. Pat. No. 6,482,820) and WO 01/03699 A1 (=U.S. 2003-0040512-A1).
Phosphonic acid substituted benzazepinone-N-acidic acid derivatives with a combined inhibitory effect on NEP and the endogenous endothelin producing system are disclosed in document EP 0 916 679 A1 (=U.S. Pat. No. 5,952,327).
Amidomethyl-substituted 1-(carboxyalkyl)-cyclopentylcarbonylamino-benzazepine-N-acetic acid derivatives which are useful e.g. for the prophylaxis and/or treatment of cardiovascular conditions or diseases, are disclosed in document WO 2005/030795 A1.
From document WO 02/094176 A2 it is known that certain compounds, including those disclosed in document EP 0 733 642 A1 and in document EP 0 916 679 A1, may inhibit the endogenous endothelin producing system via an inhibition of metalloprotease IGS5. The metalloprotease IGS5 is also known as human soluble endopeptidase (=hSEP) and is described e.g. in document WO 02/094176 A2. Further, WO 02/094176 A2 discloses the use of compounds with combined NEP/hSEP inhibitory activity for the prophylaxis or treatment of inter alia cardiovascular diseases.
Document WO 99/47138 A1 provides pharmaceutical compositions comprising a matrix metalloprotease inhibitor and a statin for the treatment of vascular diseases.
International patent application WO 2004/082636 teaches a combination of an aldosterone receptor antagonist and a neutral endopeptidase inhibitor for i.a. treatment of cardiovascular diseases.
U.S. patent application No. 2004/0092573 discloses certain HMG CoA reductase inhibitors and their combinations with further active agents.
International patent application WO 02/092622 discloses certain dipeptide derivatives which can act as dual inhibitors of ACE and NEP as well as inhibitors of the endothelin converting enzyme (=ECE). A combination of said dipeptide derivatives with i.a. HMG CoA reductase inhibitors is likewise disclosed.